Erik Melén

G protein-coupled receptors (GPCRs) play crucial roles in many biological functions in our body and they are the target of about 30% of all approved drugs. Despite advancements in technology and our understanding of molecular pharmacology, we still have much to learn about these important receptors. This includes how autoreactive antibodies (AAbs) circulating in blood can regulate in the function of GPCRs and how this contributes to human disease.  We successfully established a world-unique approach for studying full-length GPCRs for their potential to interact with other membrane proteins and antibodies, confirming their functional integrity and quality. Our knowledge about &gt

200 GPCRs allows uncover new meachanism for how AAbs recognize interacting GPCRs and how this regulates the function of GPCRs in an organ-specific manner. To address this, we willAdapt our current multiplexed analysis framework to the analysis of body fluidsDetermine the autoimmune-recognition of GPCR interactomes in longitudinal cohorts of healthy and diseased donorsReveal organ-specific description of the immune-regulation of interacting GPCRsAs an outcome, we will elucidate how GPCRs can be regulated by ligand binding, membrane interactions, and immune recognition. This will provide new learnings about the function of GPCRs, shed more light on the role of GPCRs in human health and disease, and lead to the development of more specific drugs with fewer side effects.

Background: The lungs start to develop during pregnancy and continue to grow and mature during the first 20-25 years of life. Thereafter, lung function declines due to physiological lung ageing. This lung function trajectory can be affected by host factors including diseases and exposures across the entire life-course. Sub-normal trajectories are associated with poorer health-outcomes, not only chronic airway disease (e.g. asthma and COPD) but also cardio-vascular and metabolic health, as well as premature death. Aims: The overall aim is to better predict chronic airway disease across the life-course. Here we propose that lung function charts could be used both for children and adults to monitor lung health status with time. To this end, we have recently introduced our freely available online Lung Function Tracker tool. Going forward, we hypothesize that 1) lung function trajectory modelling and long-term risk prediction of chronic airway disease will be improved by incorporating individual-level clinical, lifestyle and environmental data in the models 2) systemic biomarkers measured early in life provide prognostic values for long-term disease risk up to adulthood 3) genetics and upper airway methylation and gene expression data will give insight into mechanisms related to onset and progression of chronic airway disease As such, the specific aims in this project are: 1) To improve current lung function trajectory and risk prediction models for chronic airway disease by incorporating individual-level data 2) To identify single or combinations of systemic biomarkers measured early in life that associate with chronic airway disease 3) To identify omics features that correlate with, and predict chronic airway disease Workplan: The BAMSE study with data from 4089 participants followed from birth to age 28 years will be our primary cohort for data analysis and hypothesis testing. Blood samples, biomarkers and omics as well as clinical and lung function data are available from repeated follow-ups. Thanks to our long-term national and international collaboration, we will reach out to other cohorts for replication and validation of results, including SCAPIS. Significance: The expected outcome of the project is to develop a new prediction tool that reliably may predict long-term individual lung function trajectory and asthma/COPD risk

to identify biomarkers for early disease detection, and to elucidate mechanisms of chronic airway disease.

Lung development starts in utero and continues during childhood, and can be altered by several host and environmental factors during the life-course. A range of lung function trajectories exist in the population and sub-normal trajectories are associated with several health outcomes, including respiratory (such as asthma and COPD) and cardiovascular disease.Here we propose that lung function charts could be used both for children and adults to monitor lung health status across the life-course. To this end, we have recently introduced our freely available online “Lung Function Tracker” tool.Going forward, we hypothesize in this project thatlung function trajectory modelling and long-term risk prediction of chronic airway disease be improved by incorporating individual-level clinical, lifestyle and environmental expsure data in the modelsSystemic biomarkers measured early in life provide prognostic values for long-term disease risk up to adulthoodGenetics and upper airway methylation and gene expression data will give insight into mechanisms related to onset and progression of chronic airway diseaseThe expected outcomes of the project are 1) a new prediction tool that reliably may predict long-term individual lung function trajectory and asthma/COPD risk

2) exploration of new mechanisms of airway disease and identification of novel targets for early disease detection and 3) key genes and pathways for impaired lung function and asthma/pre-COPD will be identified.

BREATHE CAG annual report first year<br/><br/>BREATHE CAG is a clinical academic research group with a focus on obstructive lung diseases, including COPD and asthma. The research group has a broad strategy that includes basic, clinical and translational research. In 2024, the project has focused mainly on establishing the organizational structure, developing a strategy and initiating research activities. Significant progress has been made in building a solid research platform, with the recruitment of several researchers and the establishment of national and international collaborations.<br/><br/>An important milestone has been the start of a doctoral project that looks at development curves for lung function and radiomics. This includes extensive data collection from a cohort that constitutes a central data basis for the project (to be completed in 2025). The project also involves international collaboration, with planned research stays at Karolinska Institutet, SE, and Brigham and Women's Hospital, Harvard Medical School, US. Another position related to health service use for patients with obstructive lung diseases was originally advertised as a fellowship position, but after a thorough selection process it was decided to convert it into a postdoctoral position. Appointment and start are planned for the end of Q1 2025. <br/>To strengthen the organization, a CAG administrator was hired to assist with coordination and administrative tasks. Furthermore, a medical student has been engaged to process and quality assure clinical data, which will be included in several sub-projects.<br/><br/>The CAG is structured into five work packages with ongoing research activities:<br/><br/>WP1: Novel biomarkers and treatable traits<br/>Projects on radiomics, developmental curves for lung function and relationships between gut microbiome and lung health are underway. A pilot project has also been started to investigate eosinophilic subtypes in severe asthma. Funding for a further doctoral position on this topic is awaited.<br/><br/>WP2: Study trials<br/>The goal is to participate in at least two experimental studies annually. Three drug studies with inclusion in 2025 are planned. In addition, two innovation projects are under development: PREVENT-COPD, a collaboration with VitalThings AS to test home monitoring for COPD exacerbations, and AsthmaTrack, a digital outpatient clinic for asthma patients. A business case for the introduction of endobronchial valves in severe emphysema is being worked on in collaboration with Pulmonx, as well as a service and product innovation project on asthma in collaboration with Medituner and AstraZeneca. In parallel, work is being done to establish national quality registries for COPD and severe asthma.<br/><br/>WP3: Educational program<br/>A web resource is being developed to collect information about COPD and asthma for patients, relatives, healthcare professionals, researchers and industry. The project is carried out in collaboration with LHL.<br/><br/>WP4: Health services research<br/>A postdoctoral position has been established to investigate how patients with obstructive lung diseases move through the health services, and whether current practices promote or hinder health. This is done in collaboration with Regforsk at NTNU.<br/><br/>WP5: Collaboration towards HUNT5 lung<br/>The CAG leader is responsible for the lung project in HUNT5, which is planned to be implemented in 2028-2030. <br/><br/>During the year, the project group has actively participated in professional meetings, both internally and externally. Regular internal meetings ensure progress in the work, and the project has also participated in relevant international research networks. From 2025, the project will also be part of a genetic research consortium for lung function. There has been extensive application activity in the past year, with the submission of several funding proposals to various national and international calls. The project has obtained funding for some initiatives, while other applications are still under assessment. The project looks forward to further development in 2025, with a strengthened research portfolio and increased opportunities for international collaboration.<br/>

The purpose of the proposed project is to identify the key molecules and molecular pathways that underlie severe forms of SARS-CoV-2 infections.We have collected samples from several unique cohorts, including patients who have suffered from hypoxemic pneumonia, mucormycosis, multisystem inflammatory syndrome, and long COVID. We are focusing on young/pediatric patients without comorbidities, hypothesizing that monogenic inborn errors of immunity may underlie severe viral infections in otherwise healthy individuals. We will perform genetic analysis using whole exome/genome sequencing, immunological evaluation including measurement of viral-specific antibody response, autoantibody profiling, single-cell RNA and B-cell receptor sequencing, and additional relevant functional assays.The research will be carried out by four internationally recognized investigators with complementary expertise. During the initial phase, which will last for 6-12 months, patient samples will be collected, and genomic sequencing will be performed. Subsequently, immunological and other functional assays will be conducted.The project aims to identify the underlying molecular pathogenic mechanisms in patients with severe COVID-19, which could lead to better prevention strategies and more targeted therapies. Additionally, the research pipeline we develop may serve as a model for how to approach the identification of the etiological factors, pathways involved, and therapy for future pandemics.

Cardiovascular and metabolic diseases (CMD) remain the leading cause of morbidity and mortality globally, including myocardial infarction, stroke and type 2 diabetes. Although young people are not typically affected by CMD, the risk factors for these conditions are present during the early years of life, affecting long-term disease risk and the disease burden in the adulthood. Air pollution, transportation noise, and greenness are among the modifiable risk factors that may influence cardiometabolic health. Previous research on causes of CVD often focuses on single risk factors while effects from multiple environmental exposures in young adults are understudied. This project aims to investigate how air pollution, transportation noise and neighborhood greenness contribute to the development of a wide range of early markers of CMD and to elucidate characteristics that may modify the relation between environmental exposures and CMD traits. The project will be based on the prospective population-based birth cohort BAMSE comprising 4000 individuals followed from birth up to young adulthood with repeated questionnaires and extensive clinical investigations. Exposure to environmental factors is estimated based on residential address history. The results of the project will serve as a basis for policy makers in decision making processes, particularly related to environmental policies and urban planning as well as for individual risk assessment and prevention in clinical practice.